Role in pathogenesis and parasite cell biology of the trans-sialidase from Trypan

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Chagas disease, the American trypanosomiasis, is a chronic disabling parasitic disease caused by the flagellate protozoon Trypanosoma cruzi. It is considered a neglected tropical disease. With an estimated total of 100 million people at risk, about 8-10 million already infected, and about 40,000 new cases/year, Chagas disease represents a major health, social and economic problem in Latin America. The infection is naturally transmitted by triatomine vectors ("kissing bugs"), from the southern USA to the south of South America. However, chagasic patients are in fact dispersed worldwide due to migration from the endemic region to economically-developed countries. Therefore, Chagas disease is emerging in many non-endemic countries (Australia, Japan, Spain, etc). Infected people in Argentina are estimated at about 1,600,000 and in the USA at about 300,000-1,000,000. Although crucial in its life cycle, T. cruzi is unable to synthesize sialic acids. The parasite scavenges it from the mammalian host glycoconjugates through an enzyme known as trans-sialidase. This enzyme is a shed virulence factor that induces alterations in the host immune system, favoring the parasite colonization process. Our long-term aim is to fully clarify the relevance of this virulence factor to parasite biology, life cycle virulence and pathogenesis, and to understand the alterations induced on the immune system physiology. Understanding the manipulation of the immune response by pathogens allows a better fight against the infection and also helps to learn more about the immune system physiology, and eventually to transfer this knowledge to the therapeutic handling of other pathologies (autoimmune diseases, transplant rejection, inflammatory responses, etc.). This project proposes to disclose the relevance -to pathogenesis and parasite biology, at cellular and molecular levels- of the acquisition process of the sialyl residue performed by the trans-sialidase acceptor molecules on the parasite and lymphocyte surfaces. To achieve these goals we will a) use genetically-modified parasites transfected with modified transporters to accurately determine TS intracellular trafficking; b) follow the unnatural sugars approach as bioorthogonal chemical reporters to clearly identify acceptor molecules and their fate and function on parasite and white cell surfaces; c) search for the induced alterations of known immune responses using T-cell receptor transgenic and KO mice models; and d) test genetically-modified parasites to analyze the association of TS inactive isoforms with virulence factors and pathogenesis.